Thorax.us

Infectious Diseases C.difficile ISSN 1930-6741

Stephanie Swisher RN Heather P. Sneed RN

Authors

Stephanie Swisher

Heather P. Sneed

NURNP 2100 Management of Adults with Chronic and Episodic Health Problems Clinical

University of Pittsburgh School of Nursing

March 3, 2006

One of the most common nosocomial infections is caused by the clostridium difficille organism. This enteric pathogen has also been implicated as a frequent cause of illness and death among elderly inpatients. Antibiotic therapy, particularly clindamycin, ampicillin, and cephalosporins, decreases the number of normal gastrointestinal flora, thereby causing a colonization of the clostridium difficille organism resulting in an infectious colitis known as clostridium difficille associated diarrhea (CDAD).

A possible cause for frequent transmission of CDAD among inpatients is the impulsive approach to medical management of the infection. In an acute care setting, it is common for various clinicians from multiple disciplines to approach management of this illness in a variety of ways. It is a universal practice to prescribe Flagyl as a first line treatment for a CDAD; however, route, dosing and therapy duration often vary. Oral Vancomycin has also been used in the treatment of CDAD often when there is little or no symptom improvement. A recent addition to the treatment regimen is the use of an oral probiotic commercially known as Florastor, which contains the yeast Saccharomyces boulardii.

A review of the literature was completed to determine efficacy of current management strategies in the treatment of CDAD. ‘Up to date online’ was utilized to investigate data on the current treatment of CDAD. An ‘Ovid Medline’ search was performed using the key term "Clostridium-Difficile" and limiting the search to humans, English language, and abstracts between the years 2000 and 2006. Reference lists from ‘Up to Date Online’ and ‘Medline’ were reviewed and articles were selected according to their focus on the treatment of CDAD. Chosen literature had a research focus, although several case studies proved to be intriguing.

A recent systematic review from the Cochrane Database found that oral Flagyl and Vancomycin were both equally effective in obtaining both symptomatic and bacteriologic cure of

CDAD. Teicoplanin, a glycopeptide antibiotic similar to Vancomycin, was superior among other drugs in the study (Bricker, E., Garg, R., Nelson, R., Loza, A., Novak, T., and Hansen, J., 2005). However, Teicoplanin is not available in the United States. It was also reported that because of the design disparities and lack of evidence, it is reasonable to wonder if mild cases of CDAD would resolve spontaneously with supportive care alone rather than with an antibiotic. This suggestion to withhold treatment is a significant contrast to current practice.

Flagyl is the most common first line treatment in the management of CDAD.

A review of the literature performed by Aslam, Hamill, and Musher, (2005) supports current practice with Flagyl (1-1.5 grams daily) as first line treatment in the medical management of CDAD. Intravenous and oral Flagyl were discovered to be equally effective in the treatment of CDAD in a study published in 1986 by Bolton and Culshaw. However, in more recent years, the efficacy of parenteral Flagyl (500mg TID) therapy merely approached significance in the management of CDAD (Friedenberg, F., Fernandez, A., Kaul, V., Niami, P., and Levine, GM., 2001).

When comparing Vancomycin and Flagyl, some practitioners regard Vancomycin to be the superior agent in CDAD management. Studies from at least the past 15 years reveal equivalent efficacy between oral Flagyl and oral Vancomycin. Teasley, D.G., et al., (1983) found equal efficacy when comparing 10 day courses of Flagyl (250mg PO QID) and Vancomycin (500mg PO QID). In 1996, a prospective, randomized study failed to demonstrate superiority of either Flagyl or Vancomycin (Al-Eidan, F.A., McElnay, JC., Scott, M.G., Kearney, M.P., 1996). Similarly in 2000, the Queen’s University of Belfast, School of Pharmacy in Northern Ireland could not calculate a significant difference between the uses of Flagyl (400 mg

every 8 h) and Vancomycin (125 mg, 250 mg or 500 mg every 6 h) over a range of 5 to 10 days duration.

Although both oral Flagyl and Vancomycin have proven to be equally effective in the treatment of CDAD, Flagyl is preferred due to its affordability. It is less than 10 dollars for 30 tablets, whereas Vancomycin can have a cost of up to 300 dollars for 20 capsules. This means that when prescribing Vancomycin (250mg QID), the clinician must take into consideration that patients will be paying at least 600 dollars for a 10 day course of therapy versus prescribing Flagyl (500mg TID) which would be less than a 10 dollar burden on the patient (www.pepid.com, 2005). When the use of Vancomycin is warranted in the treatment of CDAD, research demonstrates that low-dose Vancomycin (125mg QID) is as effective as the high-dose (500mg QID) (Fekety, R., Silva, J., Kauffman, C., Buggy, B., and Deery, HG., 1989).

A double-blind randomized placebo controlled trial in 1994 evaluated the safety and efficacy of Florastor. When used concurrently with Flagyl or Vancomycin, the probiotic proved to be safe and effective in patients with recurrent CDAD (McFarland, LV., et al., 1994). The same results were not found in patients experiencing an initial episode of CDAD. In addition, four cases of saccharomyces cerevisiae fungemia were reported between 2000-2004 in critically ill and immunocompromised patients who were treated with Florastor (Cesaro, S., Chinello, P., Rossi, L., and Zanesco, L., 2000; Lherm, T., et al., 2002; Riquelme, AJ., et al., 2003; Cherifi, S., Robberecht, J., & Miendje, Y., 2004).

Due to the ongoing use of Flagyl and Vancomycin in the treatment of CDAD, speculation has risen as to whether resistance to these agents will be an impending concern. Although reported resistance of CDAD to Flagyl and Vancomycin has been rare, resistance has been documented. Pelaez, T., et al. (2002) found highest resistance to therapy occurs in the HIV

infected population when treated with Flagyl (12.6%). Vancomycin proves to be the preferred treatment in this population as its rate of resistance was only 4.2%. The overall rate of resistance, excluding those infected with HIV, ranges from 2.6% to 4.3% with Vancomycin being overall less resistant.

Research supports the current medical management of CDAD. Flagyl (1-1.5 grams daily X 10 days) and Vancomycin (125-500mg QID X 10 days) have equal efficacy, although Vancomycin therapy is preferred in HIV patients with CDAD secondary to less resistance. Both oral and parenteral Flagyl are effective treatments for CDAD; however, recent research proves the oral route of administration is preferred. When prescribing these as treatment regimens for CDAD, clinicians should consider ramifications of Vancomycin, such as its tremendous expense. In an effort to minimize Vancomycin expenditure, practitioners are encouraged to consider evidence that both low and high-dose Vancomycin are equally effective. Additionally, clinicians should use caution when prescribing Florastor in the critically ill and/or immunocompromised, as there have been case reports of the development of fungemia among these patients.

In conclusion, minimizing the incidence of CDAD must be the focus of future intervention. CDAD remains an ongoing clinical problem despite the use of evidence based medicine in its treatment. Second/third generation cephalosporins, Clindamycin, and Ampicillin are among known antibiotics associated with the development of CDAD (Casper, D.L., et. al., 2005). Limiting the misuse of these antibiotics will contribute to the prevention of CDAD. Therefore, practitioners should be encouraged to use a more conservative and succinct approach when instituting all antibiotic therapy.

References

Al-Eidan, F. A., McElnay, J. C., Scott, M. G., & Kearney, M. P. (2000). Clostridium difficile-associated diarrhea in hospitalized patients. Journal of Clinical Pharmacy & Therapeutics., 25(2), 101-109.

Aslam, S., Hamill, R. J., & Musher, D. M. (2005). Treatment of Clostridium difficile-associated disease: old therapies and new strategies. The Lancet Infectious Diseases, 5(9), 549-557.

Bolton, R. P., & Culshaw, M. A. (1986). Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut, 27(10), 1169-1172.

Brazier, J. S., Fawley, W., Freeman, J., & Wilcox, M. H. (2001). Reduced susceptibility of Clostridium difficile to metronidazole. The Journal of Antimicrobial Chemotherapy, 48(5), 741-742.

Bricker, E., Garg, R., Nelson, R., Loza, A., Novak, T., & Hansen, J. (2005). Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database of Systematic Reviews, 1, CD004610.

Cesaro, S., Chinello, P., Rossi, L., & Zanesco, L. (2000). Saccharomyces cerevisiae fungemia in a neutropenic patient treated with Saccharomyces boulardii. Supportive Care in Cancer,8(6), 504-505.

Cherifi, S., Robberecht, J., & Miendje, Y. (2004). Saccharomyces cerevisiae fungemia in an elderly patient with Clostridium difficile colitis. Acta Clinica Belgica, 59(4), 223-224.

Fekety, R., Silva, J., Kauffman, C., Buggy, B., & Deery, H. G. (1989). Treatment of antibiotic-associated Clostridium difficile colitis with oral vancomycin: comparison of two dosage regimens. American Journal of Medicine, 86(1), 15-19.

Friedenberg, F., Fernandez, A., Kaul, V., Niami, P., & Levine, G. M. (2001). Intravenous metronidazole for the treatment of Clostridium difficile colitis. Diseases of the Colon & Rectum, 44(8), 1176-1180.

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Lherm, T., Monet, C., Nougiere, B., Soulier, M., Larbi, D., Le Gall, C., et al. (2002). Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Medicine, 28(6), 797-801.

McFarland, L. V., Surawicz, C. M., Greenberg, R. N., Fekety, R., Elmer, G. W., Moyer, K. A., et al. (1994). A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA, 271(24), 1913-1918.

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Pelaez, T., Alcala, L., Alonso, R., Rodriguez-Creixems, M., Garcia-Lechuz, J. M., & Bouza, E. (2002). Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrobial Agents & Chemotherapy, 46(6), 1647-1650.

Riquelme, A. J., Calvo, M. A., Guzman, A. M., Depix, M. S., Garcia, P., Perez, C., et al. (2003). Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. Journal of clinical Gastroenterology., 36(1), 41-43.

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Teasley, D. G., Gerding, D. N., Olson, M. M., Petersen, L. R., Gebhard, R. L., Schwartz, M. J., et al. (1983). Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhea and colitis. The Lancet Infectious Diseases, 2(8358), 1043-1046.

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